[en] Approximately one in four newly diagnosed cancer patients receive radiation in the initial attempt to cure the tumor. In terms of the 1996 cancer incidence data, this comprises more than 350,000 patients. Inasmuch as 25% of these patients initially relapse at primary tumor sites, the issue of improving local control remains a major challenge to the profession. Recent improvements in treatment planning and delivery have enhanced the precision of radiotherapy, but radiation resistance remains a critical issue that confounds the potential for cure in many tumors. Chemical and biological modifiers of the radiation response have provided an approach with clinical promise, but their therapeutic impact remains to be established. Hence, tumor dose escalation continues to represent the most viable approach to improve local control. Recent experience with new conformal radiotherapy techniques has demonstrated that significant tumor dose escalation is feasible with concomitant reduction in normal tissue toxicity. This experience provides the best hope for immediate improvement in the rates of local tumor control. It remains, nonetheless, unclear how far the dose envelope can be pushed and whether this would be sufficient to overcome the problem of local failure. It may turn out that biological modification of the radiation response may still be necessary to provide a maximal control in certain types of tumors

[en] Impressive advances in medical technology allow earlier diagnosis and better treatment of localized prostatic cancer. Prostate cancer has also been a subject of considerable discussion in the lay press. Therefore, it is timely that we review this subject in a comprehensive fashion. This course is designed to meet the broad educational needs required for the effective care of prostate cancer patients. The faculty includes many of the leaders in the various clinical disciplines dealing with prostate cancer, and they will address a variety of scientific and clinical topics. A highlight of the course will be a discussion on the funding of new prostate cancer research initiatives. The course begins with discussions of biology, genetics, tumor markers, pathology and imaging of prostate cancer. It will cover the state-of-the-art in the management of localized prostatic cancer, including the outcomes of external beam irradiation, brachytherapy, and prostatectomy. The technique and outcome of three-dimensional conformal radiotherapy will be discussed. Radiation Therapy Oncology Group clinical trials for locally advanced prostatic cancer will be updated, and the biological rationale for combining anti-androgen therapy with radiation therapy will be presented. The use of PSA for the early detection of failure following radiation therapy is an important clinical issue. This topic will be the subject of an ASTRO consensus conference, and the conclusions will be summarized here. With the prospect for early detection of recurrences after surgery and radiotherapy using PSA, the discussions of external irradiation after surgery and of prostatectomy after radiotherapy are especially important. The course concludes with an overview of the treatment of metastatic disease

[en] Purpose: Several reports have documented the prognostic value of a post-irradiation nadir PSA of ≤1 ng/ml in prostatic cancer patients. The purpose of this study was to determine which pre-treatment and treatment-related variables impact upon achieving such nadir levels. Materials and Methods: Between January 1987 and June 1995, 740 patients with clinically localized prostate cancer were treated with 3-dimensional conformal radiotherapy (3D-CRT). 214 (29%) patients were treated with neo-adjuvant androgen ablation prior to therapy and were excluded from this analysis. Among the 526 evaluable patients, the clinical stage were as follows: T₁C=128 (24%); T₂A=76 (14%); T₂B=116 (22%); T₂C=99 (19%) and T₃=107 (21%). The prescription dose to the planning target volume (PTV) was 64.8-68.4 Gy in 87 patients (17%); 70.2 Gy in 191 (36%); 75.6 Gy in 209 (40%) and 81 Gy in 39 (7%). The median pre-treatment PSA value was 11.2 ng/ml (range 0.3-114). The median follow-up was 20 months (range: 6-76 months). Results: 242 patients (46%) had PSA levels which declined to ≤1.0 ng/ml. The median time to a nadir level of ≤1.0 was 15.6 months (range: 1-43 months) from completion of 3D-CRT. 154 (29%) patients continued to show declining PSA levels within the first 2 years after therapy, and 130 patients (25%) failed to nadir at PSA levels of ≤1.0 ng/ml. Among patients with nadir PSA levels ≤1, the 3 year PSA relapse-free survival was 91% compared to 29% for patients with nadir PSA levels >1 ng/ml (p<0.0001). A Cox-regression analysis demonstrated that nadir PSA ≤1 was the strongest predictor of PSA relapse-free survival (p<0.001) followed by Gleason score ≤ 6 (p<0.001) and stage< T3 (p=0.004). Among patients who received doses of ≥75.6 Gy, the likelihood of achieving PSA nadir levels ≤1.0 at 24 and 36 months was 86% and 93%, respectively, compared to 74 and 80%, respectively, among those who received lower doses (p<0.001). Doses of ≥75.6 Gy was the strongest independent predictor for a nadir PSA level of ≤1.0 (p<0.001) followed by pre-treatment PSA levels ≤10 ng/ml (p<0.001) and stage (p=0.01), while the Gleason score had no significant impact. Conclusion: Nadir PSA levels of ≤ 1.0 ng/ml after radiotherapy for localized prostate cancer is the strongest predictor of PSA relapse-free survival. Higher radiation doses are associated with an increased likelihood of achieving post-treatment nadir PSA levels of ≤1.0 ng/ml. Further follow-up is needed to determine whether higher doses will also translate into improved long-term outcome for these patients

[en] Purpose: Three-dimensional conformal radiotherapy (3D-CRT) has been associated with a reduction in acute and late toxicity among patients treated for localized prostatic cancer. The purpose of this study is to assess the acute and late toxicity of 3D-CRT delivered to patients in the postprostatectomy setting and to analyze which factors predict for durable biochemical control in this group of patients. Methods and Materials: Between 1988 and 1994, 42 patients were treated after prostatectomy with three-dimensional conformal radiotherapy. The median time from prostatectomy to radiotherapy was 11 months. Indications for treatment included a rising serum PSA level in 28 patients (65%) and positive surgical margins without a rising PSA level in 14 (35%). Twenty-five patients (60%) had pathologic stage T3 disease, and 32 (74%) had tumor at or close to the surgical margins. The median dose was 64.8 Gy, and the median follow-up time was 2 years. Results: 3D-CRT in the postprostatectomy setting was well tolerated. Three patients (7%) experienced Grade II acute genitourinary toxicity and nine patients (21%) experienced Grade II acute gastrointestinal toxicity during treatment. No patient experienced Grade III or higher acute morbidity. The 2-year actuarial risk for Grade II late genitourinary and gastrointestinal late complications were 5 and 9%, respectively. In patients with existing incontinence, the incidence of worsening stress incontinence 6 months after treatment was 17%, which resolved within 12 months to its preradiotherapy level in four of six cases (66%). The overall 2-year postirradiation PSA relapse-free survival rate was 53%. The 2-year PSA relapse-free survival was 66% for patients with undetectable PSA levels in the immediate postoperative period compared to 26% for those with detectable levels of PSA after surgery (p < 0.006). Furthermore, for patients with preradiotherapy PSA levels of ≤1.0 ng/ml, the 2-year PSA relapse-free survival was 74% compared to 17% of those with preradiotherapy PSA levels of >1.0 ng/ml (p < 0.002). The resection margin status, presence of seminal vesicle involvement, Gleason score, and the preprostatectomy PSA level did not impact on PSA relapse-free survival. A cox proportional hazards regression analysis demonstrated that a preradiotherapy PSA value of >1 ng/ml (p < 0.002) was the most important covariate predicting for a rising PSA after radiotherapy. Conclusions: After prostatectomy, three-dimensional conformal radiotherapy is associated with minimal treatment-related morbidity. Patients with postprostatectomy, preradiotherapy PSA levels ≤ 1.0 ng/ml, and those patients who had undetectable PSA levels in the immediate postoperative period are more likely to benefit from local adjuvant therapy

[en] Purpose: To determine the efficacy of an alpha-1 adrenoreceptor blocking agent for acute urinary symptoms in patients treated with radiotherapy for localized prostate cancer. Methods and Materials: Between 1987 and 1995, 743 patients with clinically localized prostate cancer were treated with 3D-CRT. A total of 275 (37%) patients developed Grade 2 acute urinary symptoms as defined by the RTOG morbidity scoring system. Terazosin hydrochloride (THC), a selective alpha-1 adrenoceptor blocking agent, was given to 119 (43%) patients for treatment of their urinary symptoms, whereas nonsteroidal anti-inflammatory medications (NSAID) were administered to 71 patients (26%). Thirty-one patients (11%) were treated with other medications, and 54 (20%) did not seek pharmacologic intervention for their urinary symptoms. Patients were monitored weekly to assess changes in urinary urgency, frequency, and nocturia. Results: Treatment with THC resulted in a significant resolution of urinary symptoms in 79 of 119 patients (66%), while 26 (22%) had moderate improvement, and 14 (12%) had minimal to no response to this drug. In contrast, only 11 of 71 (16%) of the patients treated with NSAIDs experienced significant symptom relief, 20 (28%) had moderate improvement, and 40 (56%) had minimal to no response. The difference in the significant symptomatic improvement between THC and NSAID therapy (66% vs. 16%) was highly significant (p < 0.001). For patients treated with THC, a higher likelihood of significant symptom relief was observed in patients who did not receive neoadjuvant androgen ablation (p = 0.04) and in those who were younger than 65 years of age (p = 0.02). Conclusion: Alpha-1 selective adrenoceptor blocking agents are effective in ameliorating the acute urinary symptoms in patients receiving radiotherapy for localized prostate cancer. Although this was not a randomized prospective study, the data suggest that NSAIDs were less effective in relieving radiation-induced urinary symptoms

[en] Purpose: To correlate the pattern of failure and subsequent survival with the technical accuracy of stereotactic brain tumor implantation. Methods and Materials: The patterns of failure of 47 consecutive patients with primary or recurrent gliomas after stereotactic implantation delivering 60 Gy via removable high activity ¹²⁵I sources were reviewed. When the tumor was covered at all levels by the chosen isodose distribution, the implant was considered to be 'ideal'. If the coverage was not complete, a numerical description of the volume of tumor outside the isodose was assigned. Criteria for 'adequate' and 'inadequate' implants were defined. Standard radiographic criteria, with pathologic confirmation in 26 cases, were used to categorize the patterns of failure into the following components: central, peripheral, distant (within the brain parenchyma), leptomeningeal, and spinal. A peripheral failure was scored as being in the 'direction of error' when the prescribed isodose did not cover the tumor volume and the subsequent tumor progression was in this region. Survival was calculated from the date of implantation. Results: Of 47 cases examined, 72% had an element of central and/or peripheral failure and 23% had a component of distant or meningeal failure. Among the patients with 'adequate' or 'inadequate' ('nonideal') implants who had a component of peripheral failure, only 19% were in the 'direction of error'. All patients with technically 'inadequate' implants progressed in both the central and peripheral region. Among the groups who had 'ideal', 'adequate', and 'inadequate' implants; 37%, 70%, and 75%, respectively, underwent reoperation [p = not significant (NS)]. Patients who underwent reoperation had a longer median survival than those who did not; 521 days vs. 298 days, respectively (p = 0.035). For patients with 'nonideal' implants, a median survival of 470 days was found for patients undergoing reoperation vs. 184 days for those who did not (p = 0.016). Conclusions: (a) Patients with 'inadequate' implants failed in both the central and peripheral region in all cases. This pattern, while less common in those with 'ideal' or 'adequate' implants, occurred in the majority of cases. (b) The technical excellence of the implant had no impact on survival. (c) Patients with 'nonideal' implants were more likely to have reoperation than those with 'ideal' implants, and this intervention was associated with a significant survival advantage

[en] Purpose: To evaluate our institution's experience using chemotherapy in conjunction with three-dimensional conformal radiation therapy (3D-CRT). Methods and Materials: From 1991 to 1998, 152 patients with Stage III non-small-cell lung cancer (NSCLC) were treated with 3D-CRT at Memorial Sloan-Kettering Cancer Center. A total of 137 patients (90%) were surgically staged with either thoracotomy or mediastinoscopy. The remainder were staged radiographically. Seventy patients were treated with radiation therapy alone, and 82 patients received induction chemotherapy before radiation. The majority of chemotherapy-treated patients received a platinum-containing regimen. Radiation was delivered with a 3D conformal technique using CT-based treatment planning. The median dose in the radiation alone group was 70.2 Gy, while in the combined modality group, it was 64.8 Gy. Results: The median follow-up time was 30.5 months among survivors. Stage IIIB disease was present in 36 patients (51%) in the radiation-alone group and 57 patients (70%) in the combined-modality group. Thirty-nine patients had poor prognostic factors (KPS<70 or weight loss >5%), and they were equally distributed between the two groups. The median survival times for the radiation-alone and the combined-modality groups were 11.7 months and 18.1 months, respectively (p=0.001). The 2-year rates of local control in the radiation-alone and combined-modality groups were 35.4% and 43.1%, respectively (p=0.1). Grade 3 or worse nonhematologic toxicity occurred in 20% of the patients receiving radiation alone and in 16% of those receiving chemotherapy and radiation. Overall, there were only 4 cases of Grade 3 or worse esophagitis. Conclusion: Despite more Stage IIIB patients in the combined-modality group, the addition of chemotherapy to 3D-CRT produced a survival advantage over 3D-CRT alone in Stage III NSCLC without a concomitant increase in toxicity. Chemotherapy thus appears to be beneficial, even in patients who are receiving higher doses of radiation therapy than are typically given with conventional techniques. Because locoregional failure remains a major challenge in patients with advanced disease, 3D-CRT in conjunction with chemotherapy may allow safe treatment to the dose levels required to further enhance local control

[en] To overcome the limitations of the intensity modulation optimization techniques based on dose criteria, we introduce a method for optimizing intensity distributions in which we employ an objective function based on biological indices. The objective function also includes constraints on dose and dose-volume combinations to ensure that the results are consistent with the physician's judgment. We apply a variant of the steepest-descent method to optimize the objective function. The method is three-dimensional and incorporates scattered radiation in the optimization process using an iterative scheme employing the pencil beam convolution method. Previously we had shown that the inverse technique of obtaining optimum intensity distributions, for which the objectives are defined in terms of a desired uniform dose to the target volume and desired upper limits of dose to normal organs, produces satisfactory approximations of the desired dose distributions for prostate plans. However, for lung, the performance of this technique was considerably inferior. Our conclusion was that, in general, it is not sufficient to specify the objectives of optimization purely in terms of a desired pattern of dose and that the objectives should also incorporate biology, perhaps in the form of biological indices. We demonstrate that the biology-based approach produces lung plans that are superior to those produced when only dose-based objectives are used. For the treatment of prostate, the two methods produce comparable dose distributions

[en] Purpose: Three dimensional conformal radiation treatments are complex, often involving large numbers of blocked or multileaf collimated fields that shape regions of high dose to conform to the treatment volume. As manual definition and digitization of aperture shapes and their corresponding multileaf configurations can be impractically time consuming, it was necessary to integrate the planning of multileaf fields into an existing three dimensional treatment planning system and improve the efficiency of treatment delivery to make these treatments feasible on a routine basis. Methods and Materials: A subfunction of the Beam's Eye View (BEV) component can be used to automatically generate a continuous aperture shape with a margin around the tumor to account for beam penumbra, and excluding any normal structures to be spared (each with its own margin). To convert a continuous aperture shape into one defined by the multileaf collimator (MLC), a leaf coverage mode is chosen to determine how leaves are fitted to aperture shapes. The conversion process also considers parameters of the specific MLC system, e.g., leaf thickness and the number of leaves. If normal structures to be shielded split the target into multiple regions, more than one multileaf aperture can result. An interactive leaf adjustment routine is also provided to allow for modification of individual leaf positions. Dose calculation programs then take into account multileaf apertures for computation of dose distributions using a pencil beam convolution model. Finally, prescription files specifying leaf and jaw configurations are prepared in treatment machine specific formats and downloaded to the computers driving the multileaf collimators and other components of the treatment machines. Results and Conclusion: An example is presented of a prostate treatment plan, with MLC configurations, dose distributions, and treatment delivery description, along with discussion of clinical implementation at Memorial Hospital

[en] Purpose: The American Society for Therapeutic Radiology and Oncology (ASTRO) published a definition for biochemical failure following treatment of prostate cancer. Others have noted difficulties with interpreting this definition and recommended modifications to accommodate special recurrence patterns. We have compared various modifications to the original ASTRO definition on our series of 1213 patients treated with transperineal permanent prostate brachytherapy. Methods and Materials: The ASTRO modifications we considered adjusted for (1) early censoring of nonrecurrent patients with rising prostate-specific antigen levels (PSA), (2) cumulative rather than consecutive rises (without a decrease) as evidence of recurrence, (3) both of the above, and (4) waiting 2 years before data analysis. The Kaplan-Meier method was used to compute the effects on recurrence rate for patients treated with and without neoadjuvant hormones. Results: With the original ASTRO definition, freedom from recurrence in our series of men who did not receive neoadjuvant hormones was 83% at 4 years. All of the modifications considered had statistically insignificant effects on freedom from recurrence rates, varying from 80% to 83% at 4 years. Patients treated with neoadjuvant hormones also showed very little sensitivity to the recurrence definition employed. Conclusion: Early censoring of equivocal patients and counting cumulative rather than consecutive rises in PSA (without a decrease) had little empiric effect on the ASTRO recurrence rates. However, we favor the addition of both these modifications to the ASTRO definition on conceptual grounds for evaluating patients following any modality (radiation or surgery), whereby a trend over multiple PSA values is used to judge failure.